The molecular basis for paroxysmal nocturnal hemoglobinuria

Yomtovian, R.; Prince, G M; Medof, M. Edward

doi:10.1046/j.1537-2995.1993.331094054626.x

Cited by 44 publications

(18 citation statements)

References 184 publications

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“…Antigens CD55 and CD59 expressed on the surface of endothelial cells can be removed by PI-PLC treatment [ 18]. This is in agreement with the finding that CD55 and CD59 expression is absent from the surface of affected erythrocytes in patients suffering from paroxysmal nocturnal haemoglobinuria, where glycolipid anchors are not expressed on their surface [19]. Hyperglycaemia is one of the major factos causing accelerated vascular and renal disease in both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus and can mediate its adverse effect through multiple pathways, one of these mechanisms being the activation of protein kinase C (PKC) by inducing increases in diglycerol levels.…”

Section: Discussionsupporting

confidence: 77%

Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells

et al. 2000

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Several lines of evidence suggest that one of the primary events in the course of diabetic vascular pathology is an alteration affecting the endothelial cell function, including abnormalities of vessel tone and permeability, coagulation, blood flow, basement membrane synthesis and turnover and the appearance of specific adhesive glycoproteins promoting the binding and migration of mononuclear cells [1,2]. Hyperglycaemia and immunological factors could trigger the development of these abnormalities [3,4].Many findings show that activation of a complement system occurs in diabetic patients. Complement Diabetologia (2000) 43: 1039±1047Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells Abstract Aims/hypothesis. This study examines whether increased glucose concentrations are responsible for a decreased expression of membrane regulators of complement activation molecules. The effect of high glucose in determining an increase in membrane attack complex deposition on endothelial cells was also investigated. Methods. Endothelial cells were isolated from umbilical cord tissue, cultured in the presence of increased concentrations of glucose, and the expression of CD46, CD55, and CD59 was detected by ELISA (enzyme-linked immunosorbent assay) and by flow cytometry. Glucose-treated endothelial cells were also incubated with antiendothelial cell antibodies and fresh complement to assess the amount of membrane attack complex formation. Results. High concentrations of glucose decreased the expression of CD59 and CD55 by endothelial cells in a time-dependent and glucose concentration-dependent manner without affecting CD46 expression. High concentrations of soluble CD59 were found in the supernatants of cells treated with high glucose. The decrease in CD59 expression induced by high glucose concentrations was reversed by coincubation of cells with a calcium channel blocking agent (Verapamil). All of these effects were not reproduced by osmotic control media. Cells treated with concentrations of high glucose were more susceptible to complement activation and membrane attack complex formation after exposure to antiendothelial cell antibodies. Conclusion/Interpretation. We speculate that hyperglycaemia could directly contribute to a loss of CD59 and CD55 molecules through a calcium-dependent phosphoinositol-specific phospholipase C activation and subsequent regulation of cell wall expression of GPI-anchored proteins. This phenomenon could facilitate the activation of a complement pathway and could play a part in the aetiology of endothelial dysfunction in diabetes. [Diabetologia (2000

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Section: Discussionsupporting

confidence: 77%

Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells

et al. 2000

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“…DAF is reportedly a functionally critical component of a lipopolysaccharide receptor complex (7). Pathology in paroxysmal nocturnal hemoglobinuria is secondary to the combined deficiency of DAF and CD59 (8).…”

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confidence: 99%

Solution structure of a functionally active fragment of decay-accelerating factor

Uhrínová

Lin

Ball

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The second and third modules of human decay accelerating factor (DAF) are necessary and sufficient to accelerate decay of the classical pathway (CP) convertase of complement. No structure of a mammalian protein with decay-accelerating activity has been available to date. We therefore determined the solution structure of DAF modules 2 and 3 (DAFϳ2,3). Structure-guided analysis of 24 mutants identified likely contact points between DAF and the CP convertase. Three (R96, R69, and a residue in the vicinity of L171) lie on DAFϳ2,3's concave face. A fourth, consisting of K127 and nearby R100, is on the opposite face. Regions of module 3 remote from the semiflexible 2-3 interface seem not to be involved in binding to the CP convertase. DAF thus seems to occupy a groove on the CP convertase such that both faces of DAF close to the 2-3 junction (including a positively charged region that encircles the protein at this point) interact simultaneously.

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“…PI is first glycosylated by uridine diphosphate (UDP)-N-acetyl-glucosamine (GluNAc) to form PI-a1,2-GluNAc [248], which is deacetylated to form PI-a1,2-GluN (GluN: glucosamine) [249]. Although not firmly established, prior or subsequent to acylation of the inositol ring of PI-a1,2-GluN, it translocates to the luninal leaflet of the endoplasmic reticulum (ER) where further glycosylation occurs by mannosylation [95,250]. Thus, the GPI core consists of three linear mannoses of which the terminal residue is capped by the transfer of PEtN from phosphatidylethanolamine [251].…”

Section: Topological Biochemistry Of Antigen Presentation By Cd1dmentioning

confidence: 99%

CD1d and natural T cells: how their properties jump-start the immune system

Joyce¹

2001

CMLS, Cell. Mol. Life Sci.

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Cellular and humoral immune mechanisms recruited to defend the host from infectious agents depend upon the early immune events triggered by antigen. The cytokine milieu within which the immune response matures is the most important of many factors that govern the nature of the immune response. Natural T cells, whose function is controlled by CD1d molecules, are an early source of cytokines that can bestow type 1 or type 2 differentiative potential upon helper T lymphocytes. This review attempts to illuminate the glycolipid antigen presentation properties of CD1d, how CD1d controls the function of natural T cells and how CD1d and natural T cells interact to jump start the immune system. CD1d is postulated to function as a sensor, sensing alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of a neo-self glycolipid, presumably by infectious assault of antigen-presenting cells, activates natural T cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jump-start the immune system.

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The molecular basis for paroxysmal nocturnal hemoglobinuria

Cited by 44 publications

References 184 publications

Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells

Glucose-induced loss of glycosyl-phosphatidylinositol-anchored membrane regulators of complement activation (CD59, CD55) by in vitro cultured human umbilical vein endothelial cells

Solution structure of a functionally active fragment of decay-accelerating factor

CD1d and natural T cells: how their properties jump-start the immune system

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